The population of the world is growing and the average age is increasing, leading to an aging population.
Cellular senescence combined with an inability of immune system to effectively eliminate senescent cells leads to persistent accumulation of senescent cells in an aging organism. On the other hand senescent cells represent a constant danger to the cell population as far as they partly lose their functions and induce malfunctioning of surrounding cells (Campisi & d'Adda di Fagagna 2007).
Albeit the portion of senescent cells is rather low even in aged tissues and reaches no more than 15% in tissues of old primates, senescent cells can produce and secrete cytokines, chemokines and extracellular proteases, which can potentially lead to detrimental changes in the entire cell population (Herbig et al. 2006; Kuilman et al. 2008). Therefore a specific state of the cell population is formed, that can be classified as senescence-associated secretory phenotype (SASP) (Coppé et al. 2008).
As senescent cells accumulate in even greater numbers over the years, the whole tissues gradually lose their specific properties. Such process results in developing of aging phenotype and encourages the risk of malignant transformation in the affected cells (Chen et al. 2005; Rodier & Campisi 2011). Hence therapies aimed to selectively eliminate senescent cells have a potential to slow down age-related changes in tissues and body in whole as well as to reduce the risks of cancer generation (Velarde & Demaria 2016; Oh et al. 2014; Naylor et al. 2013).
As reported previously, senescent cells demonstrate high resistance to apoptosis along with upregulated pro-survival signalling axes (Childs et al. 2014; Hampel et al. 2004). Several signalling axes including PI3K, BCL2 and p21 pathways are shown to be involved in senescent phenotype formation (Datta et al. 1999; Osaki et al. 2004; Minn et al. 1999; Yosef et al. 2016).
The further investigation using siRNA for silencing the key anti-apoptotic players of these networks showed the ability of such approach to specifically eliminate senescent cells from the population while preserving the rest of the population (Zhu et al. 2015). Consequently, the very same effect can be achieved when low molecular compounds are used for downregulation of senescence associated anti-apoptotic signaling networks.
Recently several low-molecular compounds which demonstrate an ability to selectively eliminate senescent cells in various tissues were proposed. This novel class of prospective drugs is referred to as senolytics. The newly identified senolytic compounds include anti-cancer agents dasatinib and navitoclax along with natural phytochemicals quercetin and tocotrienols (Zhu et al. 2015; Zhu et al. 2016; Chang et al. 2016; Malavolta et al. 2016). However, the listed compounds demonstrated diverse ability to clear senescent cells in various tissues. Dasatinib was shown to be the most effective in adipocyte progenitor cells, while Navitoclax can efficiently eliminate senescent cells in hematopoietic stem cells and muscle stem cells in mice, human umbilical vein epithelial cells, IMR90 human lung fibroblasts, and murine embryonic fibroblasts.
Quercetin and tocotrienols were more effective against senescent human endothelial cells and mouse bone marrow mesenchymal stem cells. These substantial differences in tissue specificity can be explained by the mechanism of action of these compounds. Dasatinib is multiple tyrosine kinase inhibitor, navitoclax is a BCL-family inhibitor, while quercetin and tocotrienols may affect various anti-apoptotic members of PI3K, mTOR and other signalling pathways (Montero et al. 2011; Olave et al. 2010; Bruning 2013; Gandhi et al. 2011).
Therefore thorough analysis of tissue specific signalling networks involved in survival of senescent cells may lead to bringing out novel compounds with senolytic properties specifically effective in particular tissues.
U.S. Pat. No. 7,318,938B2 discloses a composition of the plant Withania Somnifera, and, more particularly to a high purity extract composition with advantageous levels of withanolide glycosides and oligosaccharides, a minimum of polysaccharides, and substantially low levels of free withaferin A and equivalents (withanolide aglycones), which composition provides enhanced cognition-enhancing effects for the user, and an extraction process for obtaining such composition, as well as pharmaceutical, nutritional and personal care use products thereof.
There is a need to provide methods and compositions for preventing ageing.